Inflammation, mediated by the immune response to infection and sterile injury, is a major underlying cause of disease. Advances in understanding the molecular mechanisms of inflammation hold promise for developing future therapies for severe sepsis, shock, ischemia reperfusion injury, autoimmune diseases, and other debilitating diseases of national importance. Research supported by the NIGMS in the principle investigator's lab has revealed mechanisms to control inflammation by identifying and targeting specific cytokines, and by mapping and targeting specific neural circuits that control their activity. This work has now progressed to launching a new field, termed bioelectronic medicine, which holds promise as strategy to develop therapies using electronic devices to target anti-inflammatory neural circuits. The present proposal seeks to understand unanswered questions about the molecular mechanisms controlling inflammation as derived from three existing RO1 funded projects in the PI's laboratory. The first is to understand the identity and mechanisms of the reflex neural circuits that control immune responses. The second is to understand the biology of cytokine mediators of inflammation that are necessary and sufficient for disease causation. And the third is to understand the molecular mechanisms that regulate cytokine release under the influence of neurotransmitters, including regulation of cytokine gene expression and inflammasome activity. The successful completion of this work will provide significant new data necessary to develop therapeutic modalities for the prevention and treatment of inflammation using bioelectronic devices.